**2. Molecular structures of prion AGAAAAGA amyloid fibrils**

298 Recent Advances in Crystallography

(Zhang et al., 2007).

region of prions.

and Snchez-Prez, 1998; Pan et al., 1993; Reilly, 2000) belong to neurodegenerative diseases. Many experimental studies such as (Brown, 2000; Brown, 2001; Brown, 1994; Cappai and Collins, 2004; Harrison et al., 2010; Holscher, 1998; Jobling et al., 2001; Jobling et al., 1999; Kuwata et al., 2003; Norstrom and Mastrianni, 2005; Wegner et al., 2002; Laganowsky et al., 2012; Jones et al., 2012; Sasaki et al., 2008; Haigh et al., 2005; Kourie et al., 2003; Zanuy et al., 2003; Kourie, 2001; Chabry et al., 1998; Gasset et al., 1992) have shown that the normal hydrophobic region (113-120) AGAAAAGA of prion proteins is an inhibitor/blocker of prion diseases. PrP lacking this palindrome could not convert to prion diseases. The presence of residues 119 and 120 (the two last residues within the motif AGAAAAGA) seems to be crucial for this inhibitory effect. The replacement of Glycine at residues 114 and 119 by Alanine led to the inability of the peptide to build fibrils but it nevertheless increased. The A117V variant is linked to the GSS disease. The physiological conditions such as pH (Cappai and Collins, 2004) and temperature (Wagoner et al., 2011) will affect the propensity to form fibrils in this region. The 3D atomic resolution structure of PrP (106-126), i.e. TNVKHVAGAAAAGAVVGGLGG, can be looked as the structure of a control peptide (Cheng et al., 2011; Lee et al., 2008). Ma and Nussinov (2002) established homology structure of AGAAAAGA and did its molecular dynamics simulation studies. Recently, Wagoner et al. computer simulation studied the structure of GAVAAAAVAG of mouse prion protein (Wagoner, 2010; Wagoner et al., 2011). Furthermore, the author computationally clarified that prion AGAAAAGA segment indeed has an amyloid fibril forming property (Fig. 1).

**Figure 1.** Prion AGAAAAGA (113-120) is surely and clearly identified as the amyloid fibril formation region, because its energy is less than the amyloid fibril formation threshold energy of -26 kcal/mol

However, to the best of the author's knowledge, there is little X-ray or NMR structural data available to date on AGAAAAGA (which falls just within the N-terminal unstructured region (1.–123) of prion proteins) due to its unstable, noncrystalline and insoluble nature. This Chapter will computationally study the molecular modeling (MM) structures of this "Amyloid is characterized by a cross-β sheet quaternary structure" and "recent X-ray diffraction studies of microcrystals revealed atomistic details of core region of amyloid" (en.wikipedia.org/wiki/Amyloid and references (Nelson et al., 2005; Sawaya et al., 2007; Sunde et al., 1997; Wormell, 1954; Gilead and Gazit, 2004; Morley et al., 2006; Gazit, 2002; Pawar et al., 2005; and references therein). All the quaternary structures of amyloid cross-β spines can be reduced to the one of 8 classes of steric zippers of (Sawaya et al., 2007), with strong van der Waals (vdw) interactions between β-sheets and hydrogen bonds (HBs) to maintain the β-strands.

A new era in the structural analysis of amyloids started from the 'steric zipper'- β-sheets (Nelson et al., 2005). As the two sheets zip up, HPs (Hydrophobic Packings) (& vdws) have been formed. The extension of the 'steric zipper' above and below (i.e. the β-strands) is maintained by HBs (but there is no HB between the two β-sheets). This is the common structure associated with some 20 neurodegenerative amyloid diseases, ranging from Alzheimer's and type-II diabetes to prion diseases. For prion AGAAAAGA amyloid fibril structure, basing on the common property of potential energy minimization of HPs, vdws, and HBs, we will present computational molecular structures of prion AGAAAAGA amyloid fibrils.
